ABSTRACT HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most non-human species. Therefore, the most practical animal model of human AIDS consists of infection of rhesus macaques with SIVMAC or chimeras derived from SIVMAC that encode the HIV-1 envelope (SHIV). However, the usefulness of these models is limited by the fact that HIV-1 and SIVMAC are distinct viruses. Based on an understanding of species-specific restriction factors that we have acquired during the past few years, we have generated a recombinant virus, named simian tropic HIV (stHIV), that is almost entirely derived from HIV-1 but can replicate very efficiently in primary rhesus macaque cells in vitro. stHIV expresses only two proteins from SIVMAC that enable it to replicate in rhesus macaque cells in vitro and to infect rhesus macaques and replicate at low levels in vivo. The aim of this proposal is to generate improved derivatives of stHIV with enhanced ability to replicate and cause AIDS in animals. First, we will determine whether additional SIVMAC accessory proteins have a role in virus replication in vivo by introducing them into stHIV constructs. Second, we will explore an initial finding which suggests that a simple manipulation of HIV-1 should allow avoidance of restriction factors in pigtailed macaques. Third, we will reduce the SIVMAC sequences present in stHIV constructs by generating minimally mutated HIV-1 proteins that can confer resistance to macaque restriction factors. Ultimately, we will generate stHIVs that closely resemble HIV-1 strains that circulate in humans and cause AIDS in an animal model. If successful, these studies should revolutionize the preclinical exploration and development of AIDS therapeutics and vaccines. Relevance to public health HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most nonhuman primate species and current animal models are limited. We have developed novel chimeric viruses based on HIV-1 and are proposing to test their utility as an HIV-1 infection model in monkeys and to generate additional HIV-1- derived viruses. If successful, this proposal will lead to improved animal models for HIV-1 infection and will considerably facilitate the development and testing of drug and vaccine interventions.